Photoelectrochemical oxidative C(sp3)−H borylation of unactivated hydrocarbons

Organoboron compounds are of high significance in organic synthesis due to the unique versatility of boryl substituents to access further modifications. The high demand for the incorporation of boryl moieties into molecular structures has witnessed significant progress, particularly in the C(sp3)−H borylation of hydrocarbons. Taking advantage of special characteristics of photo/electrochemistry, we herein describe the development of an oxidative C(sp3)−H borylation reaction under metal- and oxidant-free conditions, enabled by photoelectrochemical strategy. The reaction exhibits broad substrate scope (>57 examples), and includes the use of simple alkanes, halides, silanes, ketones, esters and nitriles as viable substrates. Notably, unconventional regioselectivity of C(sp3)−H borylation is achieved, with the coupling site of C(sp3)−H borylation selectively located in the distal methyl group. Our method is operationally simple and easily scalable, and offers a feasible approach for the one-step synthesis of high-value organoboron building blocks from simple hydrocarbons, which would provide ample opportunities for drug discovery.

The Manuscript by Xia, Guo and co-authors describes a terminal oxidant and transition metal-free, photoelectrochemical C(sp3)-H borylation.This method involves intermolecular hydrogen atom transfer by the chlorine radical, generated via anodic oxidation of chloride, and followed by photoinduced homolysis of the produced chlorine gas.The resulting alkyl radical was trapped with diboron reagent to afford alkyl boronates.Expectedly, this method exhibits high selectivity towards terminal C-H sites.This operationally simple and scalable protocol can be employed for broad range of substrates including halides, silanes, ketones and esters.
I think this work does not represent significant advances to meet the high standard of Nature Communications for the following reasons.This method involves known photoelectrochemical strategy (Ref: 14) for radical generation.It exhibits alike site-selectivity, as in previous radical C-H borylation reports (Ref: 64), and in the authors' recent work, which is not sited in this manuscript (J.Am.Chem. Soc. 2023, 145, 7600-7611).
The major concern of this research is raised from the discussion/interpretation of the unconventional selectivity and related reaction mechanism.The authors observed similar selectivity for several substrates as Aggarwal's published work (ref 64).And the authors rationalized such unconventional selectivity by steric effect only, e.g.primary over tertiary borylation.Accordingly, the authors proposed the generation of "free" chlorine radical for the following HAT.However, clearly the observed regioselectivities in the borylation indicate that "free" chlorine radicals are unlikely to be the predominant HAT species.(J.Am.Chem.Soc.80, 4997-5001 (1958).J. Org.Chem.63, 63, 8860-8864 (1998).) Response: We are very grateful for the reviewer's careful review and kind suggestion.To understand the unconventional selectivity and related reaction mechanism, several mechanistic studies have been performed, as shown below (also compiled in Fig. 5 of the revised manuscript).

1) H/D scrambling experiment
According to existing literature reports, Cl radicals undergo HAT based on their inherent selectivity (tertiary>secondary>primary), but more substituted radicals react slower with certain electrophilic reagents, resulting in faster functionalization of primary radicals.This means that the formation of alkyl radicals is reversible (or alkyl can be "isomerized" by subsequent reversible HAT with other molecules of the substrate) and rapid (consistent with KIE value 1).We validated this conclusion through H/D scrambling experiments.The following three deuterated compounds (S55-d, S56-d, and S57-d) were synthesized with moderate to high levels of deuterium incorporation at the tertiary sites, based on the method developed by Wu and colleagues (Chem. Sci. 2020, 11, 8912).
We chose S55-d (with 58% deuterium incorporation at the tertiary site), S56-d (with 93% deuterium incorporation at the tertiary site), and S57-d (with 85% deuterium incorporation at the tertiary site) as suitable substrates for the H/D scrambling experiment.As shown in the following scheme, substrate S55-d undergoes C(sp 3 )-H borylation reaction under the standard conditions to obtain the corresponding borylated product 55-d in 52% yield.As expected, C(sp 3 )-H borylation only occurred at the terminal methyl group and significant H/D perturbations were observed, with only 23% D-incorporation at the tertiary site (35% lower than the original D-incorporation).The reaction of S56-d as substrate achieved similar results (36% lower than the original Dincorporation at the tertiary site), and the reaction of S57-d also achieved similar results (27% lower than the original D-incorporation at the tertiary site).All these results indicate that the reaction can preferentially form tertiary carbon radicals at first.Due to the slower reactivity of these more substituted radicals with certain radical acceptors, the primary carbon radicals are subsequently generated through a reversible HAT process and then react with B2(cat)2 to achieve the unconventional site selectivity.

2) Regioselectivity studies on the reaction of n-pentane i) Effect of B2(cat)2 stoichiometry
Procedure: To a 10 mL vial equipped with a stir bar was added B2(cat)2 (0.05-0.40 mmol, 0.5-2.0equiv.),Et4NCl (0.1 mmol,0.5 equiv.),and HCl (concentrated,0.8 mmol,4.0 equiv.).MeCN (6 mL) was then added followed by the addition of n-pentane (2.0 mmol, 10 equiv.).The reaction mixture was stirred at 680 rpm, irradiated with 390 nm LED lamps and 2.0 mA electrolysis for 12 h.The reaction temperature was maintained at approximately room temperature by cooling with a desk fan.After irradiation, a solution of pinacol (71 mg, 0.60 mmol, 3.0 equiv.)and Et3N (0.84 mL,6.0 mmol,30 equiv.) in CH2Cl2 (1 mL) was added and stirring was continued for 1 h.Add trimethoxybenzene (internal standard) to the reaction mixture.After 1 minute of vigorous oscillation, filter 0.20mL of the crude reaction mixture through a silica short plug and determine the yield through GC analysis.

iii) Effect of n-pentane stoichiometry
Procedure: To a 10 mL vial equipped with a stir bar was added B2(cat)2 (48mg, 0.2 mmol, 1.0 equiv.),Et4NCl (0.1 mmol,0.5 equiv.),and HCl (concentrated,0.8 mmol,4.0 equiv.).MeCN (6 mL) was then added followed by the addition of n-pentane (0.6-10.0 mmol, 3.0-50.0 equiv.).The reaction mixture was stirred at 680 rpm, irradiated with 390 nm LED lamps and 2.0 mA electrolysis for 12 h.The reaction temperature was maintained at approximately room temperature by cooling with a desk fan.After irradiation, a solution of pinacol (71 mg, 0.60 mmol, 3.0 equiv.)and Et3N (0.84 mL,6.0 mmol,30 equiv.) in CH2Cl2 (1 mL) was added and stirring was continued for 1 h.Add trimethoxybenzene (internal standard) to the reaction mixture.After 1 minute of vigorous oscillation, filter 0.20mL of the crude reaction mixture through a silica short plug and determine the yield through GC analysis.

3) Regioselectivity studies on the reaction of 2,3-dimethylbutane (DMB)
Since the chlorine radical-mediated HAT step has proved to be not turnover-limiting through our KIE experiment, we hypothesized that the afforded regioselectivity is highly dependent on the choice of radical acceptors.To testify our hypothesis, we chose 2,3-dimethylbutane (DMB), a branched isomer of hexane that was recently utilized to probe the HAT species by Zuo (J.Am.Chem.Soc. 2020, 142, 6216−6226;J. Am. Chem. Soc. 2023, 145, 359−376)

An electron paramagnetic resonance (EPR) experiment has been performed to detect key radical intermediates by adding a free radical spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO). From the afforded EPR spectroscopy (as shown below) it is suggested that carbon radicals are generated and rapidly captured by DMPO to form relatively stable free radicals (g = 2.007, AN = 14.81 G, and AHβ = 21.38 G). All the above mechanistic experiments supported the engagement of chlorine radical species and formation of carbon-centered radicals via intermolecular HAT process in the photoelectrochemical C(sp 3 )-H borylation reaction.
Procedure: To a 10 mL vial equipped with a stir bar was added B2(cat)2 (48 mg, 0.2 mmol, 1.0 equiv.),Et4NCl (0.1 mmol,0.5 equiv.),and HCl (concentrated,0.8 mmol,4.0 equiv.).MeCN (3 mL) was then added followed by the pentane (2.0 mmol, 10 equiv.).The reaction mixture was stirred at 680 rpm, irradiated with 390 nm LED lamps and 2.0 mA electrolysis.

5) Explanation of HAT species
To gain more insight into the origination of HAT species, styrene (60) was added into the photoelectrochemical system and a chlorine-containing ketone product 61 that captured chlorine radical species at the terminal alkene was successfully isolated in 69% yield, indicating the generation and involvement of chlorine radicals during our reaction process.Consistent with this finding, the electrolysis of a solution of N,N-diallyltosylamine ( 62), HCl, and Et4NCl in CH3CN produced the chlorinated ring-closing product 63 derived from a chlorine radical addition-5-exotrig cyclization-hydrogenation sequence (for the last hydrogenation step in electrochemical system, please see a related reference: Angew.Chem.Int. Ed. 2016, 55, 2226−2229).However, in the presence of B2(cat)2, the formation of borylated compound 63' via chlorine radical addition-5-exotrig cyclization-borylation sequence was not detected.All these results suggest the involvement of chlorine radical species in the reaction process.
Procedure: To a 10 mL vial equipped with a C anode (φ = 3 mm), a platinum plate cathode (10 x 10 x 0.1 mm), and a magnetic stir bar was added with styrene (60, 0.3 mmol, 1 equiv).After three cycles of evacuation and backfilling of the reaction flask with argon, a solution of Et4NCl (0.15 mmol, 0.5 equiv) in CH3CN (6 mL) and HCl (concentrated, 1.2 mmol, 4 equiv) were added.The electrolysis was carried out in dark using a constant current of 2 mA at room temperature until complete consumption of styrene.The reaction mixture was concentrated in vacuo and purified by flash column chromatography.The target compound was obtained with a yield of 69%.All recorded spectroscopic data matched those previously reported in the literatures.
After three cycles of evacuation and backfilling of the reaction flask with argon, a solution of Et4NCl (0.15 mmol, 0.5 equiv) in CH3CN (6 mL) and HCl (concentrated, 1.2 mmol, 4 equiv) were added.
The electrolysis was carried out in dark using a constant current of 2 mA at room temperature until complete consumption of compound 62.The reaction mixture was concentrated in vacuo and purified by flash column chromatography.The target compound was obtained with a yield of 57%.
As for the SI, more GC spectra should be provided to clarify the unconventional selectivity.
More than 20 substrates showed the unconventional selectivity, however, only 8 examples are provided with GC spectra.
Response: We are very grateful for the reviewer's careful review and kind suggestion.We have added the corresponding GC spectra into the revised SI.

Reviewer #2
The authors present an interesting approach to the oxidative C(sp3)−H borylation of hydrocarbons using photoelectrochemistry, eliminating the need for metals and oxidants.Response: We are very grateful for the reviewer's careful review and kind suggestion.We have added very detailed mechanistic studies and in-depth understanding of the afforded site selectivity into the revised manuscript (please see Fig. 5 in the revised manuscript as well as the answer to Reviewer #1).

Add results with less hydrocarbons to Table 1. The use of large excess of hydrocarbons is a
major limitation although simple alkanes can be recovered.

Response:
We are very grateful for the reviewer's careful review and good suggestion.We have added the corresponding results with less hydrocarbons in the revised Table 1 (entry 14).The yield of alkyl boronate 3 slightly decreased (58%) when the reaction was performed using 5.0 equiv. of cyclohexane 1.

Explain the drastically different results with nBu4NCl and Et4NCl.
Response: We are very grateful for the reviewer's careful review and kind suggestion.The use of nBu4NCl instead of Et4NCl would promote the hydrolysis of B2(cat)2 as well as other side reaction process.Following the advice, we have conducted some research to investigate the origin of the drastic difference on yield with the use of nBu4NCl and Et4NCl.When using nBu4NCl to replace Et4NCl for reaction, no target borylated product was detected.We have found significant differences in the 1 H NMR spectra obtained by studying two different electrolytes.When using Et4NCl for the photoelectrochemical reaction, the 1 H NMR spectrum was very clean and no obvious by-products were detected.However, when nBu4NCl was used for the reaction, the 1 H NMR spectrum showed the formation of hydrolysis product (catechol) of B2cat2 together with some other unknown byproducts.We have added the relevant experimental results to the revised SI.
i) Fig. 1 shows the 1 H NMR spectra of B2(cat)2 and catechol in CDCl3 Fig. 1 1 H NMR spectra of B2(cat)2 and catechol in CDCl3 ii) NMR spectra of reaction mixtures with Et4NCl or nBu4NCl: To two 10 mL vials equipped with stir bars was added B2(cat)2 (48mg, 0.2 mmol, 1.0 equiv.),Et4NCl nBu4NCl (0.1 0.5 equiv.), and HCl (concentrated, 0.8 mmol, 4.0 equiv.).MeCN (6 mL) was then added followed by the pentane (2.0 mmol, 10 equiv.).The reaction mixture was stirred at 680 rpm, irradiated with 390 nm LED lamps and 2.0 mA electrolysis.The reaction temperature was maintained at approximately room temperature by cooling with a desk fan.Before the start of the reaction, samples were picked up from these two vials for NMR analysis (time = 0 h, see Fig. 2).
After the reaction mixture was stirred at 680 rpm and irradiated with 390 nm LED lamps for 8 h, irradiation was stopped and samples were picked up from these two vials for NMR analysis (time = 8 h, see Fig. 3).

CF3OH or CF3CH2OH?
Response:We are very grateful for the reviewer's careful review and kind suggestion.When CF3OH is used as solvent, the yield of alkylboron 3 is 39%.The use of CF3CH2OH as solvent delivered alkylboron 3 in 27% yield.We have added these results in the revised Table 1 (entries 10-11).

ClB(cat) was important for Aggarwal's work. It is important here?
Response: We are very grateful for the reviewer's careful review and good suggestion.It is possible to utilize the commercially available ClB(cat) as the chlorine source and initiate a radical chain process.Although the reaction with ClB(cat) instead of HCl gave no desired borylated product in an undivided-cell reaction, it works in a divide cell to deliver product 3 in 8% yield with the use of 50 mol% ClB(cat) instead of HCl, and Et4NBF4 instead of Et4NCl.However, considering the high price of ClB(cat), our photoelectrochemical method shows greater advantages.
Procedure: To a 10 mL divide cell equipped with a stir bar, in anodic chamber was added B2(cat)2 (48 mg, 0.20 mmol, 1.0 equiv.),Et4NBF4 (0.10 mmol, 0.5 equiv.), and ClBcat (0.10 mmol, 0.5 equiv.) in MeCN (6 mL) followed by cyclohexane (2.0 mmol, 10 equiv.).In cathodic chamber was added Et4NBF4 (0.10 mmol, 0.5 equiv.)and MeCN (6 mL).The reaction mixture was stirred at 680 rpm, irradiated with 390 nm LED lamps and 2.0 mA for only 2 h, and a reaction sample was picked up for the post-processing of GC analysis.The yield of the target product 3 was found to be 8%.After 8 h irradiation and electrolysis, the yield did not increase.
6.There is no evidence that 57 is formed through addition of a chlorine atom to styrene.

Response:
We are very grateful for the reviewer's careful review and kind suggestion.We have added another chlorine radical-trapping experiment in order to illustrate the involvement of Cl radical species in the reaction process.The electrolysis of a solution of N,N-diallyltosylamine (62), HCl, and Et4NCl in CH3CN produced the chlorinated ring-closing product 63 derived from a chlorine radical addition-5-exo-trig cyclization-hydrogenation sequence (for the last hydrogenation step in electrochemical system, please see a related reference: Angew.Chem.Int. Ed. 2016, 55, 2226−2229).However, in the presence of B2(cat)2, the formation of borylated compound

What are the limitations?
Response: The limitation of this photoelectrochemical protocol is that the reaction cannot be well applied to nitrogen-containing hydrocarbon substrates.For example, we have tested amides, amines, and sulfonamides under the standard conditions, but the reaction of using these compounds as substrates cannot yield the desired C-H borylated products.We have added one sentence to describe this limitation in the revised manuscript.

390 nm LED is purple LED not blue LED.
Response: We are very grateful for the reviewer's careful review and kind suggestion.We have corrected this error.

It is inaccurate to describe tetraethylammonium chloride as electrolyte and HCl as the chlorine source. They both provide chloride and increase conductivity. HCl is needed likely to increase proton reduction to avoid reduction of the boron reagent. What if you use other acids, such as TFA, TfOH.
Response: We gratefully acknowledge the reviewer for this very constructive suggestion, which undoubtedly facilitates the explanation of the reaction mechanism.In order to further understand the role of HCl in this photoelectrochemical system, several control experiments were carried out, as shown in Fig. 5g of the revised manuscript.Replacing HCl with other inorganic chloride salts, such as NaCl, CsCl, and LiCl, was found to be ineffective.Although the use of other acids instead of HCl, such as TFA and TfOH, led to complete loss of reaction efficiency (Table 1, entry 15), substituting HCl by H3PO4 successfully gave the desired C-H borylated product 3 in 67% yield, which indicates that HCl mainly plays a crucial role as proton source rather than chlorine source.At the cathode surface, protons undergo cathodic reduction to generate H2, and protect the substrate B2(cat)2 from single-electron reduction in certain conditions (J.Am.Chem. Soc. 2021, 143, 12985−12991).
Moreover, a divided-cell experiment was carried out.Substrates 1 and 2, along with Et4NCl, HCl, and CH3CN, was placed into the anode chamber, while Et4NCl and CH3CN were added into the cathode chamber.As expected, upon light irradiation and electrolysis for 12 h the desired product 3 was detected in the anode chamber with 46% yield, suggesting that the photoelectrochemical C(sp 3 )-H borylation occurred surrounding the graphite rod anode.Interestingly, a moderate yield (41%) of alkyl boronate 3 was still afforded in the absence of HCl at the anode chamber, probably because the B2(cat)2 reagent in the anode chamber of divided-cell would not be electrochemically reduced, and therefore it does not need the protection of HCl any more.The protons that come from trace amount of H2O in the cathode cell are combined with electrons at the cathode to generate H2.

Please give more details on the components of the photoelectrochemical cell to allow others to reproduce the resutls.
Response: We are very grateful for the reviewer's careful review and kind suggestion.More details about the photochemical equipment and electrochemical cell have been added to the revised SI.

Reviewer #3
The Manuscript by Xia, Guo and co-authors describes a terminal oxidant and transition metal-free, photoelectrochemical C(sp 3 )-H borylation.This method involves intermolecular hydrogen atom transfer by the chlorine radical, generated via anodic oxidation of chloride, and followed by photoinduced homolysis of the produced chlorine gas.The resulting alkyl radical was trapped with diboron reagent to afford alkyl boronates.Expectedly, this method exhibits high selectivity towards terminal C-H sites.This operationally simple and scalable protocol can be employed for broad range of substrates including halides, silanes, ketones and esters.Response: We are very grateful for the reviewer's careful review and kind suggestion.Our recent work about C-H borylation reaction (J.Am. Chem. Soc. 2023, 145, 7600-7611) has been cited in the revised manuscript as ref.65.In comparison to our previous work using iron catalyst and NFSI as oxidant, the newly reported photoelectrochemical protocol is metal free (the Pt cathode does not participate in the reaction, and can be replaced by a graphite rod electrode with slight decrease of reaction efficiency) and sustainable, which is more welcomed by the pharmaceutical industries as it is mandatory to remove toxic trace metal contaminants from products.Gram-scale synthesis of alkylboron product has been performed on a 20 mmol scale in continuous-flow, which greatly highlights the synthetic potential of our method.Furthermore, very detailed mechanistic studies and in-depth understanding of the afforded site selectivity have been added into the revised manuscript, including the EPR measurement, H/D scrambling experiment, radical trapping reactions, as well as the investigations of the HAT species.Based on this newly added mechanistic results, we believe that this protocol has exhibited some novel aspect compared to Aggarwal's and our previous C-H borylation reaction .Therefore we really appreciate it if you could reconsider our new submission.

I think this work does not represent significant advances to meet the high standard of
To verify whether a Cl-boron complex can be generated in the photoelectrochemical system, a divided-cell experiment was carried out, as shown in the figure below.Substrates (1) and B2cat2 (2), along with Et4NBF4, ClBcat, and CH3CN, was placed into the anode chamber, while Et4NBF4 and CH3CN were added into the cathode chamber.As expected, upon light irradiation and electrolysis for 12 h the desired alkyl boronate 3 was detected in the anode chamber with 8% yield, suggesting that the photoelectrochemical C(sp 3 )-H borylation occurred surrounding the graphite rod anode.Interestingly, an increased yield (24%) of alkyl boronate 3 was afforded in the presence of H2O (5 μL) at the anode chamber, probably because the presence of H2O promotes the generation of HO-Bcat species from Cl-Bcat, and HO-Bcat is the key precursor for the production of Cl-boron complex (Path A; generation of Cl-boron complex from HO-Bcat and Cl radical; Path B; generation of Cl-boron complex from O(Bcat)2 and Cl radical).
Another evidence for the Cl-boron complex as HAT species is afforded by using squalane (S59) as substrate.The reaction of squalane (S59) with B2cat2 (2) under the standard photoelectrochemical conditions successfully delivered the desired C(sp 3 )-H borylation product 59 in 43% yield with exclusive site selectivity.In the meantime we were also able to isolate a terminal alkene 59' as a major side product, which is likely to be generated from 1° radical species followed by anodic oxidation and E1 elimination (see the figure below), while the generation of internal alkene 59'' was not observed.Considering the fact that Cl radical preferentially undergoes HAT at the 3° C(sp 3 )-H bonds and a Cl-boron complex preferentially undergoes HAT at the sterically unhindered 1° C(sp 3 )-H bonds, the formation of this terminal alkene 59' proves the existence of Cl-boron complex as HAT species in our photoelectrochemical system.
13 C NMR (101 MHz, Chloroform-d) δ 121.2, 108.6, 39.5, 37.5, 37.4, 32.9, 28.1, 27.6, 26.0, 24.9,   24.6, 22.9, 22.8, 19.9.     1 H NMR spectrum (400 MHz, CDCl3)  3) Radical-mediated C(sp 3 )−H borylation of n-pentane Using benzylidenemalononitrile (64) and phenyl acrylate (66) as typical radical acceptors instead of B2cat2 (2) under our photoelectrochemical conditions, the preferential formation of 3° C-H alkylated products 65 and 67 has already revealed that site selectivity of C(sp 3 )−H functionalization reaction is radical acceptor depended.In order to answer the reviewer's question about whether regioselectivity of C−H borylation is also determined by the HAT species, we further investigate C(sp 3 )−H borylation reaction of n-pentane.Considering the differential features of Cl radical (secondary C−H seletivity) and Cl-boron complex (primary C−H seletivity) in the HAT process, we compare the regioselectivity results of currently existing protocols for C(sp 3 )−H borylation of npentane.From the scheme below we can see that all the reactions show good distal methyl selectivity, which is mainly caused by the radical acceptor depended nature.If we look more closely, the C(sp 3 )−H borylation reactions show better α-C(sp 3 )−H selectivity in the presence of metal species.It may be due to the fact that the presence of metal species plays a key role in the cleavage of boronboron bond of B2cat2 and promotes the formation of key Cl-boron complex.Considering that HAT is a fast process in our photoelectrochemical system (KIE: kH/kD = 1.0) as well as the fact that 33% yield of secondary boronate is generated, this result suggests that both free Cl radical and Cl-boron complex as HAT species could exist in our reaction system.
In addition, we found that the unconventional selectivity of C(sp 3 )−H borylation reaction is not only determined by HAT species or radical acceptor.There are many other factors that could greatly affect the site selectivity of the photoelectrochemical reaction, such as equivalents of borylating agent, alkane substrate, HCl, and concentration of the reaction.Please see the figure below, as well as more details in the revised SI (2.12.Regioselectivity studies with n-pentane).

4) Conclusion
Based on the above results, we propose that free Cl radical-mediated and Cl-boron complexmediated HAT processes are both likely to exist in our photoelectrochemical system.We have corrected the proposed mechanism, as shown in the scheme below as well as in the revised manuscript (see Fig. 6).On the basis of fast and reversible HAT and the trapping experiments with benzylidenemalononitrile and phenyl acrylate, we believe that the free Cl radical-mediated HAT is the dominant during our photoelectrochemical reaction process.Based on the above mechanistic studies and relevant literature reports, we propose the plausible mechanism outlined in Fig. 6.First, the Cl -is electrochemically oxidized to Cl2 at the anode surface, and then the chlorine radical species (A) is generated via light-promoted homolytic cleavage of Cl2.According to its inherent selectivity, the chlorine radical undergoes HAT process with C(sp 3 )-H compounds (taking S9 as an example) to initially release a more substituted carbon-centered radical (B), which could not proceed with the C-H borylation reaction at the tertiary site, probably due to steric hindrance.Since the alkyl radical formation is reversible (or the alkyl radical can "isomerize" by performing the subsequent reversible HAT with other molecules of the substrate) and fast, a sterically unhindered primary radical (D) is generated and trapped by B2(cat)2 to give an alkyl boronate ester (E) as well as the ligated boryl radical (F) (Path A).Alternatively, the HO-Bcat (G) generated by hydrolysis and anodic oxidation in the reaction system can be complexed with Cl radical species (A) to obtain Cl-radical-boron "ate" complex (H), followed by the HAT process to obtain carbon center radical (D) (Path B).Treating intermediate E with pinacol and triethylamine finally delivers the desired product 9.At the cathode surface, protons undergo cathodic reduction to generate H2, obviating the need for sacrificial oxidants.
2. From a methodology aspect, this research involves a known photoelectrochemical strategy (Ref: 14) for radicals generation.Moreover, the unconventional selectivity for radical borylation has been reported in several reports (e.g.ref 64, 65).It is not significant to the field and related fields, unless the above-mentioned questions in 1 could be answered.Otherwise, this investigation is just an synthetic extension of ref 14.
Response: We are very grateful for the reviewer's comments.As far as we know, the direct one step photoelectrochemical transformation of simple hydrocarbons into alkyl boronates was previously not known, and our protocol shows the advantages of simple conditions and scalability in comparison to the current C(sp 3 )−H borylation protocols using stoichiometric oxidants (Nature 2020, 586, 714−719; J. Am.Chem. Soc. 2023, 145, 7600−7611) or stoichiometric metal catalysts (Chem. Commun. 2023, 59, 7108−7111;J. Am. Chem. Soc. 2023, 145, 15207-15217).Furthermore, in-depth mechanistic studies including the exploration of the HAT species and site selectivity for C(sp 3 )−H borylation have been extensively carried out.Given the significance and versatility of organoboron compounds in organic synthesis as well as the novel feature of photoelectrochemical transformation, we really appreciate it if you could reconsider our research work for publication in Nature Communications.

Reviewer #2 (Remarks to the Author):
The authors have addressed previous comments.To ensure replicability of the outcomes, it is crucial to furnish comprehensive details about the flow reactor, including its design, operating conditions, and specific parameters.This will facilitate an accurate recreation of the experiment in different settings.
Response: We are very grateful for the reviewer's positive comments and great suggestion.We have provided the details about the flow reactor, including its design, operating conditions, and specific parameters.All these information have been added into the revised SI.

Procedure for gram-scale reaction in continuous flow
Note: The design is shown in Figure S3.The flow electrolysis cell is assembled using two aluminum bodies ( and , 120 mm x 110 mm x 8 mm) with a groove (70 mm x 60 mm x 8 mm).The main material of  is translucent quartz glass (70 mm x 60 mm x 3 mm). is a reaction module with internal reaction electrodes ( With grooves, 70 mm x 60 mm x 5 mm), and the external material is mainly polytetrafluoroethylene.  is a Graphene module with grooves (Thickness is 10 mm).flow reactor: 120 * 110 * 50mm.

Figure S4. Flow reaction device setup
To ensure that the system is in an oxygen free state, a pump is first used to fill the entire pipeline with acetonitrile in a nitrogen atmosphere, during which a high flow rate is required to eliminate bubbles.Then place the degassed reaction bottle into the reactor.Electrolysis is a Electrolytic cell equipped with graphite anode and graphite cathode.The constant current is 10 mA, the volume is 6 cm 3 , and the distance between electrodes is 2mm.Use a pump to flow through the Electrolytic cell at a flow rate of 0.1 mL/min.Use a dry Round-bottom flask at the outlet to collect the reaction liquid, and then use Pinacol and triethylamine for post-treatment.
it possible the radical chain mechanism is propagated by the reaction of chloride-stabilised boryl radical as the same or similar intermediate proposed by Aggarwal (ref 64).Obviously, more mechanistic studies should be conducted.For example, the authors could refer to Aggarwal's published work (ref 64).Response: We are very grateful for the reviewer's careful review and good suggestion.It is possible to utilize the commercially available ClB(cat) as the chlorine source and initiate a radical chain process.Although the reaction with ClB(cat) instead of HCl gave no desired borylated product in an undivided-cell reaction, it works in a divide cell to deliver product 3 in 8% yield with the use of 50 mol% ClB(cat) instead of HCl, and Et4NBF4 instead of Et4NCl.
compounds hold immense potential in organic synthesis, and the development of an efficient and versatile method for their synthesis is of high importance.One of the primary strengths of this study is the broad substrate scope and interesting regioselectivity of C(sp3)−H borylation, with a preference for the distal methyl position.The scalability of the procedure makes it even more appealing, as it facilitates access to high-value organoboron building blocks from simple hydrocarbons in a single step.I recommend accepting this article for publication after minor revisions.The authors should address the following points:1.Provide more details on the mechanism of radical borylation and how it leads to the observed regioselectivity.The HAT process with chlorine atom is expected to be much less selective.Likely, only selected carbon radicals made their way to the organoboron products.
Nature Communications for the following reasons.This method involves known photoelectrochemical strategy (Ref: 14) for radical generation.It exhibits alike site-selectivity, as in previous radical C-H borylation reports (Ref: 64), and in the authors' recent work, which is not sited in this manuscript (J.Am.Chem.Soc.2023, 145, 7600-7611).

Figure S5 .
Figure S5.Design of the flow reactor for the gram-scale reaction , illuminated with a 390 nm LED lamp, and electrolyzed at 2.0 mA for 12 hours.Maintain the reaction temperature at approximately room temperature by cooling with a desktop fan.After irradiation, a solution of pinacol (71 mg, 0.60 mmol, 3.0 equiv.)andEt3N(0.84mL, 6.0  mmol, 20 equiv.)inCH2Cl2 (1 mL) was added and stirring was continued for 1 h.The intrinsic selectivity of 1°/3° C(sp 3 )−H bonds was determined by 1 H NMR analysis.